Interaction between P450 eicosanoids and nitric oxide in the control of arterial tone in mice.
OBJECTIVE
Epoxyeicosatrienoic acids (EETs) serve as endothelial-derived hyperpolarizing factors (EDHF), but may also affect vascular function by other mechanisms. We identified a novel interaction between EETs and endothelial NO release using soluble epoxide hydrolase (sEH) -/- and +/+ mice.


RESULTS
EDHF responses to acetylcholine in pressurized isolated mesenteric arteries were neither affected by the sEH inhibitor, N-adamantyl-N'-dodecylurea (ADU), nor by sEH gene deletion. However, the EDHF responses were abolished by catalase and by apamin/charybdotoxin (ChTx), but not by iberiotoxin, nor by the cytochrome P450 inhibitor PPOH. All four EETs (order of potency: 8,9-EET >14,15-EET approximately 5,6-EET >11,12-EET) and all 4 dihydroxy derivatives (14,15-DHET approximately 8,9-DHET approximately 11,12-DHET >5,6-DHET) produced dose-dependent vasodilation. Endothelial removal or L-NAME blocked 8,9-EET and 14,15-DHET-dependent dilations. The effects of apamin/ChTx were minimal. 8,9-EET and 14,15-DHET induced NO production in endothelial cells. ADU (100 microg/mL in drinking water) lowered blood pressure in angiotensin II-infused hypertension, but not in L-NAME-induced hypertension. Blood pressure and EDHF responses were similar in L-NAME-treated sEH +/+ and -/- mice.


CONCLUSIONS
Our data indicate that the EDHF response in mice is caused by hydrogen peroxide, but not by P450 eicosanoids. Moreover, P450 eicosanoids are vasodilatory, largely through their ability to activate endothelial NO synthase (eNOS) and NO release.
Hercule
Hantz C
HC
Charité Campus Buch, Franz Volhard Clinic/ECRC, Berlin, Germany.
Schunck
Wolf-Hagen
WH
Gross
Volkmar
V
Seringer
Jasmin
J
Leung
Fung Ping
FP
Weldon
Steven M
SM
da Costa Goncalves
Andrey Ch
ACh
Huang
Yu
Y
Luft
Friedrich C
FC
Gollasch
Maik
M
D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology*; D001685:Biological Factors / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D002374:Catalase / Q000378:metabolism; D018999:Charybdotoxin / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015777:Eicosanoids / Q000494:pharmacology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004851:Epoxide Hydrolases / Q000172:deficiency / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009129:Muscle Tonus / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D001685:Biological Factors; D065607:Cytochrome P-450 Enzyme Inhibitors; D015777:Eicosanoids; D010455:Peptides; C067410:endothelium-dependent hyperpolarization factor; D018999:Charybdotoxin; D009569:Nitric Oxide; C064719:iberiotoxin; D003577:Cytochrome P-450 Enzyme System; D006861:Hydrogen Peroxide; D002374:Catalase; D004851:Epoxide Hydrolases; D019331:NG-Nitroarginine Methyl Ester